This application to the NIH high end instrumentation program requests an Orbitrap Fusion Lumos with electron transfer dissociation (ETD); a new generation Orbitrap Tribrid mass spectrometer to be released on the market immediately after the proposal deadline. Through a non-disclosure agreement (expiring May 31, 2015), we have obtained a quote for this game-changing instrument for proteomic analysis, including 5-fold sensitivity improvement and 40% higher ETD efficiency compared with the current state-of-the-art Orbitrap Fusion Tribrid. With the assistance of the manufacturer (Thermo Fisher Scientific) we seek to custom fit this instrument with infrared multiphoton dissociation (IRMPD). The sought new generation Orbitrap Tribrid is further capable of precursor ion selection down to 0.4 amu without analyte loss for greatly improved selectivity. The proposed users (7 major, 9 minor) represent six different University of Michigan (UM) Departments, all in close geographical proximity on the UM central campus, which is entirely void of infrastructure for shared proteomic analysis. UM has strong track records in both biomedical research and mass spectrometry (MS) technologies that enable breakthroughs in basic biomedical and disease science. The proposed users focus on analyzing disease- associated multiprotein complexes through crosslinking/MS, quantifying disease-associated changes in protein posttranslational modifications, small volume trace analysis of peptides, lipids, and metabolites, as well as discovery and mechanistic/structural interrogation of natural product biosynthetic pathways. The described, NIH- funded (17 R01, three R37, one DP2, two U01, and one P50 grant) research projects will leverage the unique group of world-class MS experts at UM to develop/extend the utility of the Orbitrap Fusion Lumos, including the custom IRMPD capability, thus providing additional benefits in the form of new methodologies and techniques. The proposed instrument will be housed within an expanded MS facility, being developed into an MS Center of Excellence, within the UM Department of Chemistry. This facility is highly used by researchers throughout the region, but still operates with out-of-date instruments that range between 20 to 40 years old, and is thus in desperate need of the upgrade described in this proposal. Operation and maintenance of the instrument will be performed both by existing highly qualified staff in the Chemistry Department MS facility, but also by a new dedicated PhD-level staff person funded by the College of Literature, Science and the Arts (LSA), representing a total five year staff commitment of ~$1,000,000. In addition, various UM units have provided cost sharing for two years of service for the instrument (in addition to the year one warranty), after which time we expect that instrument recharge costs from major/minor users will support instrument operations within the Chemistry MS Facility, including contributions to partial funding (~60%) of the Facility staff. The remaining 40% of staff salaries will continue to be covered by LSA. Furthermore, UM LSA has agreed to renovate the existing MS facility space in preparation for the requested Orbitrap Fusion Lumos to maximize its productivity and use.